The invention relates to the Lewis acid catalyzed rearrangement of boronate complexes to boronic esters. More particularly, the invention relates to the rearrangement of boronate complexes having the general structure (I) to boronic esters having the general structure (II) in accordance with the following equation: ##STR1## where each of R.sup.1, R.sup.4 and R.sup.5 independently, is an organic group as defined more fully hereinbelow, where X is a nucleofugic group, i.e., a group subject to nucleophilic displacement, such as a halogen, and particularly chlorine or bromine, where R.sup.2 is H, a lower alkyl or X, where R.sup.3 is an organic group (as defined more fully hereinbelow) or X, and where R.sup.4 and R.sup.5 may be the same or different and may be directly linked, so that the boronic ester is cyclic.
The process of the present invention is particularly useful when R.sup.4 and R.sup.5, or the linked group OR.sup.4 --R.sup.5 O, are chiral groups.
In another aspect, the invention relates to the preparation of .alpha.-halo boronic esters, including chiral .alpha.-halo boronic esters by the room temperature, Lewis acid catalyzed, conversion or rearrangement of boronic esters (III) to homologous .alpha.-halo boronic esters (V) and (VI) by way of intermediate borate anions (IV) which can be formed by reacting the boronic esters (III) at cryogenic temperatures with a dihaloalkylmetal reagent. This aspect of the invention may be characterized by the following equation: ##STR2## where R.sup.1, R.sup.4 and R.sup.5 are the same as above, X is halogen and R.sup.6 is H or lower alkyl.
In still another aspect of the invention, the .alpha.-halo boronic esters (V) and (VI) can be prepared by a room temperature Lewis acid catalyzed rearrangement of boronate complexes (IV) which have been prepared at about 0.degree. C. (as opposed to cryogenic temperatures, i.e., about -70.degree. to -100.degree. C.) by reacting the boronic esters (III) with a dihalomethane and a strong, sterically hindered base, such as a metal dialkyl amide, a metal triphenylmethane, or a metal bis(trialkylsilyl)amide. This aspect of the invention may be characterized by the following equation: ##STR3## where R.sup.1, R.sup.4, R.sup.5 and X are the same as set forth above, and each of R.sup.7 and R.sup.8, which may be the same or different, is an alkyl group, preferably a secondary alkyl group such as cyclohexyl or isopropyl.
The present invention is useful for the preparation of a variety of compounds including insect sex attractants, enzyme inhibitors, antibiotics, pharmaceuticals, and other substances having significant biological activity, where the biological activity depends upon the absolute configuration of one or more chiral carbon atoms in the molecule. Thus, an insect sex attractant which can be prepared in accordance with the present invention is chemically identified as (3S,4S)-4-methyl-3-heptanol (from Scolytus multistriatus, the European elm bark beetle). Another example is the principal component of the aggregation pheromone of the western pine beetle, Dendroctonus brevicomis, which is chemically known as exo-brevicomin. Each of these compounds contains two chiral centers, and the compounds are attractive to the respective insect species only when the chiral centers both have the correct, natural configuration.
The process of the present invention is also useful for the synthesis of an .alpha.-acetamido boronic acid, (.alpha.S)-.alpha.-acetamido-.beta.-phenylethaneboronic acid, which is a potent inhibitor of enzymes known as serine proteases, demonstrated first with chymotrypsin. See Matteson et al., J. Am. Chem. Soc., Vol. 103, pp 5241-2(1981). By use of the present invention, improved yields and purities of the intermediates leading to the .alpha.-amido boronic acids can be achieved.
It is to be understood that the novel aspects of the present invention reside in the rearrangement of the various boronate complexes (I) and (IV) at about room temperature in the presence of Lewis acid catalyst which exhibits sufficient acid strength to complex the nucleofugic group X of the boronate complex, yet insufficient acid strength to destroy boronic ester groups associated therewith. Particularly suitable Lewis acid catalysts have been found to include anhydrous zinc chloride and ferric chloride. Mixtures of these and other Lewis acids also may be used.
It is to be understood, further, that the manner in which the boronate complex are prepared is not essential to the present invention, and that complexes formed by any known technique may be employed. For example, as disclosed in Matteson et al., J. Am. Chem. Soc., Vol. 102, pp 7588-7590 (1980) and Matteson et al., J. Am. Chem. Soc., Vol. 102, pp 7590-7591 (1980), the boronate complexes may be prepared by reacting a boronic ester (III) with a dihaloalkylmetal, such as dichloromethyl lithium. The dichloromethyl lithium may be preformed at approximately -100.degree. C. and allowed to react with the boronic ester at that temperature, or the dichloromethyl lithium may be generated in the presence of and rapidly captured by the boronic ester to form the boronate complex at temperatures of about -78.degree. C.
It has also been suggested that dichloromethyl lithium may be prepared by contacting a strong, sterically hindered base, such as an alkali metal dialkylamide, of which lithium dicyclohexylamide is an example, with dichloromethane in the presence of a ketone solvent (Taguchi et al., J. Am. Chem. Soc., Vol. 96, pp 3010-3011 (1974).
Neither of the above Matteson et al. articles suggests the use of a catalyst, and the Taguchi et al. article does not discuss the preparation of boronic esters. However, the Matteson et al. articles indicate that the use of a chiral boronic ester can substantially bias the selectivity of the disclosed non-catalytic process toward formation of the (.alpha.S) .alpha.-chloro boronic ester at the expense of the (.alpha.R) isomer, or vice versa. Specifically, it is disclosed that if ##STR4## is the cyclic chiral boronic ester group BO.sub.2 C.sub.10 H.sub.16 (+) which can be prepared from the cis diol derived from (+)-.alpha.-pinene by osmium tetroxide catalyzed hydroxylation and which is referred to as "(+)-pinanediol", then the (.alpha.S)-.alpha.-chloroboronic ester can be produced in significant excess over the (.alpha.R)-.alpha.-chloroboronic, ratios of (.alpha.S)/(.alpha.R) in the range 3:1 to 25:1 having been observed with a variety of groups R.sup.1 (methyl, n-butyl, cyclohexyl, phenyl, and others). It is further known from Rathke et al., J. Organomet. Chem., Vol. 122, pp 145-149 (1982) that borate complexes (IV) can be generated from dichloromethaneboronic esters, ##STR5## and alkyllithium reagents, R.sup.9 Li, where R.sup.9 is lower alkyl, and that the boronate complexes so formed rearrange to .alpha.-chloro boronic esters (V) and (VI).